Mesenchymal Stem Cell Administration Attenuates Colon Cancer Progression by Modulating the Immune Component within the Colorectal Tumor Microenvironment
Mesenchymal Stem Cell Administration Attenuates Colon Cancer Progression by Modulating the Immune Component within the Colorectal Tumor Microenvironment
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DOI：
10.1002/sctm.18-0117
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发表时间：
2019-03-01
影响因子：
6
通讯作者：
Chapel, Alain
中科院分区：
文献类型：
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作者：
Francois, Sabine;Usunier, Benoit;Chapel, Alain
我们在这里确定间充质干细胞（MSC）治疗对实体瘤进展的影响。在人类结直肠癌细胞以及代表人类病理学的免疫活性大鼠结直肠癌发生模型中研究了 MSC 的影响。使用骨髓（BM）来源的间充质干细胞进行治疗，可增加无肿瘤动物的数量，并将肿瘤的数量和大小减少一半，从而显着减少癌症的发生和进展，从而延长其寿命。癌症进展的减弱是由间充质干细胞调节免疫成分的能力介导的。具体来说，在 MSC 治疗的大鼠的腺癌 (ADK) 中，CD68+ 单核细胞/巨噬细胞的浸润减少了 50%，而 CD3+ 淋巴细胞的存在几乎增加了一倍。间充质干细胞将巨噬细胞重新编程为参与吞噬作用的调节细胞，从而抑制促炎细胞因子的产生。此外，MSC 还降低了 NK（自然杀伤）和 rTh17 细胞活性、Treg 募集、CD8+ 淋巴细胞和内皮细胞的存在，同时恢复了 Th17 细胞活性。 miR-150 和 miR-7 的表达增加了五倍，表明这些 miRNA 在调节肿瘤生长中可能发挥作用。重要的是，间充质干细胞的施用限制了健康组织的损伤并减弱了放射治疗后的肿瘤生长。综上所述，我们在此表明间充质干细胞通过调节肿瘤微环境的免疫成分对结肠癌的发展具有持久的作用。此外，我们还确定了两种与 MSC 减弱癌症生长能力相关的 miRNA。
We here determine the influence of mesenchymal stem cell (MSC) therapy on the progression of solid tumors. The influence of MSCs was investigated in human colorectal cancer cells as well as in an immunocompetent rat model of colorectal carcinogenesis representative of the human pathology. Treatment with bone marrow (BM)-derived MSCs significantly reduced both cancer initiation and cancer progression by increasing the number of tumor-free animals as well as decreasing the number and the size of the tumors by half, thereby extending their lifespan. The attenuation of cancer progression was mediated by the capacity of the MSCs to modulate the immune component. Specifically, in the adenocarcinomas (ADKs) of MSC-treated rats, the infiltration of CD68+ monocytes/macrophages was 50% less while the presence of CD3+ lymphocytes increased almost twofold. The MSCs reprogrammed the macrophages to become regulatory cells involved in phagocytosis thereby inhibiting the production of proinflammatory cytokines. Furthermore, the MSCs decreased NK (Natural Killer) and rTh17 cell activities, Treg recruitment, the presence of CD8+ lymphocytes and endothelial cells while restoring Th17 cell activity. The expression of miR-150 and miR-7 increased up to fivefold indicating a likely role for these miRNAs in the modulation of tumor growth. Importantly, MSC administration limited the damage of healthy tissues and attenuated tumor growth following radiotherapy. Taken together, we here show that that MSCs have durable action on colon cancer development by modulating the immune component of the tumor microenvironment. In addition, we identify two miRNAs associated with the capacity of MSCs to attenuate cancer growth.